This study began as an efficacy study of interferon alpha-2a in patients with hairy cell leukemia. It was observed that most patients responded to interferon, but that very few complete responses were being obtained. Studies being done elsewhere confirmed the low complete remission rate. Once interferon was stopped, nearly uniformly disease progression requiring reinstitution of therapy was observed. There appear to be very few if any patients who will not require further therapy after receiving 12 or 18 months of continuous interferon treatment. Because of these findings, we opted to administer interferon continuously to patients who were initially responsive to this drug. Of the 53 evaluable patients (of the 56 entered on this study), there was one complete remission, 41 partial remissions, 1 minor response, 9 patients with stable disease and only 1 patient with disease progression. Fourteen patients continue to receive interferon without interruption with a median duration of continuous interferon treatment of 9.2 years. Thirty-four patients discontinue interferon for a variety of reasons, the most common being the development of acquired interferon resistance in association with interferon antibodies. The resistance to interferon was manifest early, in the first 18 months of treatment, except in two cases. An important finding in this study is the continued slow, but significant, hematologic improvement in absolute granulocyte and platelet counts beyond 18 months of therapy, thereby indicating that prolonged treatment results in continued benefit rather than the production of antibodies with subsequent development of interferon resistance. Although it is clear from this study that hairy cell leukemia can be controlled in the long-term with interferon, longer follow-up will be necessary to determine if continuous therapy with interferon is better than intermittent therapy.